Salt generates antiinflammatory Th17 cells but amplifies pathogenicity in proinflammatory cytokine microenvironments
Julia Matthias, … , Thomas Korn, Christina E. Zielinski
Julia Matthias, … , Thomas Korn, Christina E. Zielinski
Published June 2, 2020
Citation Information: J Clin Invest. 2020;130(9):4587-4600. https://doi.org/10.1172/JCI137786.
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Research Article Immunology Inflammation

Salt generates antiinflammatory Th17 cells but amplifies pathogenicity in proinflammatory cytokine microenvironments

Abstract

Th cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here, we demonstrate that high-NaCl conditions induced a stable, pathogen-specific, antiinflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and IL-17A expression in high-NaCl conditions. The NaCl-induced acquisition of an antiinflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high-NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a proinflammatory and TGF-β–low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.

Authors

Julia Matthias, Sylvia Heink, Felix Picard, Julia Zeiträg, Anna Kolz, Ying-Yin Chao, Dominik Soll, Gustavo P. de Almeida, Elke Glasmacher, Ilse D. Jacobsen, Thomas Riedel, Anneli Peters, Stefan Floess, Jochen Huehn, Dirk Baumjohann, Magdalena Huber, Thomas Korn, Christina E. Zielinski

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Figure 7

TGF-β governs the reciprocal enhancement of pro- versus antiinflammatory Th17 cell functions by NaCl in vitro and in vivo in an EAE mouse model.

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TGF-β governs the reciprocal enhancement of pro- versus antiinflammatory...
(A) Naive murine CD4+ T cells from 2D2 mice were cultured in vitro in neutral (Th0) or various Th17-polarizing conditions (Th17), including TGF-β in low- or high-NaCl conditions, and analyzed by FACS on day 3.5 for IL-17A and FoxP3 expression. Representative dot plots show intracellular IL-17A and FoxP3 expression after restimulation of the cells with PMA and ionomycin. (B) Intracellular IL-17A and FoxP3 expression was quantified as in A. (C) Clinical EAE scores (0–5) were determined after adoptive transfer of T cells (1.5 × 106) that were polarized in vitro for 3.5 days with TGF-β and IL-6 (both 25 ng/mL) in high- or low-NaCl conditions. (D and E) Naive murine CD4+ T cells were cultured as in A in the absence of exogenous TGF-β. Representative dot plots and summary plots are shown. (F) Clinical EAE scores after adoptive transfer of T cells (2 × 106) that were polarized in vitro for 3.5 days with IL-1β, IL-6, and IL-23 in high- versus low-NaCl conditions. *P < 0.05, A 2-tailed, paired Student’s t test was performed for pairwise comparisons of low- and high-NaCl conditions (n = 3–4 mice; data are representative of at least 3 independent experiments) (B and E) and 2-way ANOVA with Bonferroni’s multiple comparisons test (C and F).